In recent years, stimuli-responsive polymers have been widely used for drug delivery system (DDS), various separating agents, catheter, artificial muscle, chemovalve, etc. and thus have been of growing importance. For example, JP-A-8-103653 (The term “JP-A” as used herein means an “unexamined published Japanese patent application”) discloses a polymer which changes in its higher order structure to swell or shrink in an aqueous solution by the action of heat, light or by a change in pH or potential as a stimuli-responsive polymer. Specifically, acrylamide or methacrylamide derivatives such as poly-N-isopropylacrylamide, N,N-diethylacrylamide and N-isopropylmethacrylamide, and vinylethers such as vinyl methyl ether are disclosed as a polymer having an upper critical solution temperature (UCST) or a lower critical solution temperature (LCST) with respect to water, which swells or shrinks in response to a temperature change.
Although these known polymers which swell or shrink in response to a temperature change are described as having an upper critical solution temperature (UCST) or a lower critical solution temperature (LCST), they all have, in fact, a lower critical solution temperature (LCST). In other words, at a temperature of not lower than the lower critical solution temperature, these polymers reversibly undergo agglomeration of polymers that renders themselves insoluble in water. On the contrary, at a temperature of not higher than the lower critical solution temperature, these polymers can be dissolved in water. For example, poly-N-isopropylacrylamide (PNIPAM), which is applied to DDS, etc. at present, has a lower critical solution temperature of 32° C. in an aqueous solution. When this polymer is allowed to gel, it reversibly undergoes swelling and shrinkage depending on the temperature developed by heat.
A polymer having a lower critical solution temperature (LSCT) shrinks at a predetermined temperature or higher and thus is disadvantageous in that it can be hardly adjusted so as to meet the demand for shrinkage at low temperature (preferably not higher than the body temperature) in the application to DDS, separating agent, etc.
However, all these known thermo-responsive polymers such as poly-N-isopropylacrylamide are stimuli-responsive polymers having a lower critical solution temperature (LCST) which respond only to thermal stimulation. Thus, these thermo-responsive polymers can neither switch a lower critical solution temperature to an upper critical solution temperature (UCST) nor have, in a single compound, both functions of causing their reversible dissolution and precipitation depending on the hydrogen ion concentration, when they respond to heat.
On the other hand, as the polymer which changes in its higher order structure by a pH change there is known a polyacrylic acid or polymethacrylic acid. However, these compounds contain carboxylic acid, which has electric charge, and thus are disadvantageous in that a separating agent comprising such a polymer adsorbs compounds other than desired compounds (non-specific adsorption) and thus cannot provide efficient separation and purification.
If a composite stimuli-responsive polymer which can switch between a lower critical solution temperature (LCST) and an upper critical solution temperature (UCST) or have, in a single compound, both functions of causing its reversible dissolution and precipitation depending on the hydrogen ion concentration can be obtained, the above described adjustment can be easily conducted. The appearance of such a polymer has been desired particularly in an art requiring fine adjustment because such a thermo-responsive polymer can be more widely used.
Further, if used as a separating agent for protein inert to heat, etc., the conventional polymer agglomerates when heated, causing denaturation of protein.
Moreover, if the polymer is used as DDS (e.g., chemical-releasing capsule) by encapsulating a chemical in its gel, it is necessary that the affected part be cooled to allow the gel to swell and release the chemical upon releasing. However, it is practically easy to raise, rather than cool, the temperature of the affected part.
Further, if a thermo-responsive polymer is used as DDS, it needs to exhibit an upper critical solution temperature (UCST) in physiological saline. In this respect, an interpenetration polymer network (IPNa) of polyacrylic acid and polyacryloyl glycinamide is known as a thermo-responsive polymer which exhibits an upper critical solution temperature (UCST) in an aqueous solution (Makromol. Chem., Rapid Commun. 13, 557-581 (1992)). However, this polymer does not exhibit any upper critical solution temperature (UCST) in physiological saline.
Therefore, the appearance of a thermo-responsive polymer which agglomerates when heated in an aqueous solution and exhibits an upper critical solution temperature (UCST) even in physiological saline has been desired.